chr18-57545828-A-AG

Variant names:

• chr18-57545828-A-AG
• rs201434287
• NM_000140.5:c.*4883_*4884insC

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_000140.5(FECH):​c.*4883_*4884insC variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00627 in 152,252 control chromosomes in the GnomAD database, including 15 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: 𝑓 0.0063 (15 hom., cov: 32)
• Consequence: FECH NM_000140.5 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.35
• Publications: 0 publications found

Genes affected

FECH (HGNC:3647): (ferrochelatase) The protein encoded by this gene is localized to the mitochondrion, where it catalyzes the insertion of the ferrous form of iron into protoporphyrin IX in the heme synthesis pathway. Mutations in this gene are associated with erythropoietic protoporphyria. Two transcript variants encoding different isoforms have been found for this gene. A pseudogene of this gene is found on chromosome 3.[provided by RefSeq, May 2010]

FECH Gene-Disease associations (from GenCC):

• protoporphyria, erythropoietic, 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• autosomal erythropoietic protoporphyria

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP6: Variant 18-57545828-A-AG is Benign according to our data. Variant chr18-57545828-A-AG is described in ClinVar as Likely_benign. ClinVar VariationId is 327329.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.051 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000140.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FECH	NM_000140.5	MANE Select	c.*4883_*4884insC		3_prime_UTR	Exon 11 of 11	NP_000131.2	P22830-1
	FECH	NM_001012515.4		c.*4883_*4884insC		3_prime_UTR	Exon 11 of 11	NP_001012533.1	P22830-2
	FECH	NM_001374778.1		c.*4883_*4884insC		3_prime_UTR	Exon 10 of 10	NP_001361707.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FECH	ENST00000262093.11	TSL:1 MANE Select	c.*4883_*4884insC		3_prime_UTR	Exon 11 of 11	ENSP00000262093.6	P22830-1
	FECH	ENST00000652755.1		c.*4883_*4884insC		3_prime_UTR	Exon 11 of 11	ENSP00000498358.1	P22830-2

Frequencies

GnomAD3 genomes AF: 0.00622 AC: 947 AN: 152134 Hom.: 15 Cov.: 32

Gnomad AFR AF: 0.000821

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0300

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.0564

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00904

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000647

Gnomad OTH AF: 0.00478

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.00627 AC: 954 AN: 152252 Hom.: 15 Cov.: 32 AF XY: 0.00729 AC XY: 543 AN XY: 74450

African (AFR) AF: 0.000818 AC: 34 AN: 41556

American (AMR) AF: 0.0305 AC: 467 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3470

East Asian (EAS) AF: 0.0563 AC: 292 AN: 5182

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4812

European-Finnish (FIN) AF: 0.00904 AC: 96 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000647 AC: 44 AN: 67994

Other (OTH) AF: 0.00473 AC: 10 AN: 2114

Alfa AF: 0.00410 Hom.: 3

Bravo AF: 0.00948

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Protoporphyria, erythropoietic, 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-2.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs201434287; hg19: chr18-55213060;